The present invention relates to pharmacologically active compounds and to their use as medicaments. More particularly it has been found that the sterol derivatives described herein can be used for regulating meiosis.
In L. F. Fieser and M. Fieser: Steroids; Reinhold Publishing Corporation, 1967, 5xcex1-bromocholest-ane-3xcex2,6xcex2-diol; 7xcex1-bromocholestane-3xcex2,6xcex1-diol; 7xcex1-bromocholestane-3xcex2,6xcex2diol; 7xcex1-bromo-cholestane-3xcex2,5xcex1-diol-6-one; 7xcex2-bromocholestane-3xcex2,5xcex1-diol-6-one; 3xcex2-bromocholestane-2xcex1-ol; 5xcex1-chlorocholestane-3xcex2,6xcex1-diol; 5xcex1-chlorocholestane-3xcex2,6xcex2-diol; 6xcex2-chlorocholestane-3xcex2,-5xcex1-diol; xcex947,9(11)-cholestadiene-3xcex2,6xcex1-diol; xcex947,9(11)-cholestadiene-3xcex2,6xcex2diol; cholestane-2xcex1,3xcex1-diol; cholestane-2xcex1,3xcex2-diol; cholestane-2xcex2,3xcex1-diol; cholestane-2xcex2,3xcex2-diol; cholestane-3xcex1,4xcex1-diol; cholestane-3xcex1,4xcex2-diol; cholestane-3xcex2,4xcex2-diol; cholestane-3xcex1,5xcex1-diol; cholestane-3xcex2,5xcex1-diol; cholestane-3xcex2,6xcex1-diol; cholestane-3xcex2,6xcex2-diol; cholestane-3xcex2,22xcex1-diol, cholestane-3xcex2,22xcex2-diol; cholestane-3xcex2,7xcex1,8xcex1-triol; xcex945-cholestene-3xcex2,4xcex1-diol; xcex945-cholestene-3xcex2,4xcex2-diol; xcex945-cholestene-3xcex2,20xcex1-diol; xcex945-cholestene-3xcex2,22xcex1-diol; xcex945-cholestene-3xcex2,22xcex2-diol; xcex945-cholestene-3xcex2,24xcex1-diol; xcex945-cholestene-3xcex2,24xcex2-diol; xcex946-cholestene-3xcex2,5xcex1-diol; xcex948(14)-cholestene-3xcex2,9xcex1-diol; xcex9411-cholestene-3xcex1,24-diol; xcex945-cholestene-3xcex2,6-diol-7-one; xcex945-cholestene-4xcex1-ol-3-one; xcex945-cholestene-3xcex2,4xcex2,7xcex1-triol; coprostane-3xcex1,5xcex2-diol; coprostane-3xcex2,5xcex2-diol; coprostane-3xcex2,6xcex2-diol; coprostane-4xcex2,5xcex2-diol-3-one and 20xcex2-hydroxy-20-isocholesterol are mentioned in the subject index.
In German patent application having publication no. 1,183,079, a process for preparing 4xcex1-hydroxy-5a-cholestan-3-one is mentioned in Example 5. This compound is not stated to have any utility other than as an intermediate.
In German patent application having publication no. 1,224,738, cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate-6xcex2-acetate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate-6xcex2-formiate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-sulphate and cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-phosphate are mentioned in Examples 1-5, respectively. It is mentioned that the compounds described therein can be used for the treatment of arteriosclerosis.
In German patent application having publication no. 2,201,991 C2, a process for the preparation of insecticides such as 2xcex2,3xcex2,14xcex1,22(R),25-pentahydroxycholest-7-en-6-one is described.
German patent application having publication no. 2,236,778 B2 relates to a novel insecticide, i.e., cholest-7-en-2xcex2,3xcex2,5xcex2, 11xcex1,14xcex1,20(R)-heptahydroxy-6-one.
In German patent application having publication no. 2,409,971 B2, 5,24-cholestadien-3xcex2-ol; 5-cholesten-3xcex2,24,25-triol-3xcex2-acetate; 5-cholesten-3xcex2,24,25-triol-3xcex2,24-diacetate; 5,25-cholestadien-3xcex2-ol acetate; 5-cholesten-3xcex2,25,26-triol-3xcex2-acetate and 5-cholesten-3xcex2,25,26-triol are mentioned in Examples 1, 1, 2, 3, 3 and 6, respectively. It is mentioned that the compounds described therein are valuable intermediates for the technical preparation of 24,25(or 25,26)-dihydroxycholecalciferol.
In German patent application having publication no. 2,453,648B2, cholest-5xcex1-an-3xcex2,6xcex1-diol; cholest-5xcex2-an-3xcex2,6xcex2-diol; cholest-5xcex1-an-3,6-dione; cholest-5xcex1-an-6xcex2-ol-3-one and cholest-5xcex1-an-2xcex1-bromo-6xcex2-ol-3-one are mentioned as intermediates in column 6.
In German patent application having publication no. 2,415,676, cholestan-3p,25-diol-3xcex2-acetate; cholestan-3xcex2,5xcex1,25-triol-3xcex2-acetate; cholestan-3xcex2,5xcex1,25-triol; cholestan-5xcex1,25-diol-3-one; cholest-4-en-25-ol-3-one and cholesta-4,6-dien-25-ol-3-one are mentioned as compounds III, IV, X, Xl XII and XIII, respectively. It is suggested that the compounds described therein may be substantially stronger that vitamin D3.
In German patent application having publication no. 2,546,715 A1, a process for preparing 1xcex1,3xcex2dihydroxycholest-5-en and 1xcex1,3xcex2-dihydroxycholest-6-en is mentioned in Example 1 (compounds V and II). It is suggested that the compounds described therein are useful additives to foodstuff and can be used in vitamin compositions.
In German patent application having publication no. 2,822,486A1, 3xcex1,6xcex1-dihydroxy-5xcex2-cholestan-24-one; 3xcex1,6xcex1,24-trihydroxy-5xcex2-cholestan; 3-chlorocholest-5,24-dien; 3xcex2-hydroxycholest-5-en-24-on acetate and 3-chlorocholest-5-en-24-on are mentioned in Example 3,4,5a and 6c and as formula VlI, respectively. It is mentioned that the compounds described therein can be used as intermediates for the preparation of desmosterin, derivatives thereof and other active vitamin D.
In German patent application having publication no. 3,241,172 A1, cholestan-25-fluoro-3xcex2,22(S)-diol; cholestan-25-chloro-3xcex2,22(S)-diol; cholestan-25-methyl-3xcex2,22-diol; cholestan-25-methyl-3xcex2,22-diol-3-hydrogenbutandioate and cholestan-25-methyl-3xcex2,22-diol-bis-hydrogenbutandioate are mentioned in claims 2, 3, 5, 6 and 7, respectively. It is mentioned that the compounds described therein inhibit the activity of HMGCOA reductase and the formation of blood cholesterol.
In German patent application having publication no. 3,390,016C2, a process for preparing 1xcex1,25-dihydroxy-26,26,26,27,27,27-hexafluorocholes-5-en is described. It is mentioned that this compound can easily be converted into a compound having vitamin D3 like activity.
In Danish patent application having publication no. 123,767, a process for preparing 2xcex2,3xcex2,14xcex1,22,25-pentahydroxy-xcex947-5xcex2-cholesten-6-one is mentioned. It is mentioned that the compounds described therein have an action on the central nervous system.
In European patent application having publication no. 15,122 B1, 25-hydroxy-3xcex2-[(tetrahydro-2H-pyran-2-yl)oxy]cholest-5-en-24-on; 3xcex2[(tetrahydro-2H-pyran-2-yl)oxy]cholest-5-en-24-on; 25-hydroxy-24-oxocholesterol-3xcex2-acetate; 24-oxocholesterol-3xcex2-acetate; 25-hydroxy-24-oxocholesterol; 24,25-dihydroxycholesterol; 3xcex1,6xcex1,25-trihydroxy-24-oxo-5xcex2-cholestane; 1xcex1,25-dihydroxy-24-oxocholesterol; 1xcex1,24,25-trihydroxycholesterol; 3xcex2-hydroxy-24-oxo-cholesta-5,7-dien; 3xcex2,25-dihydroxy-24-oxocholesta-5,7-dien; 3xcex2-hydroxy-24-oxocholesta-5,7-dien; 1xcex1,3xcex2-dihydroxy-24-oxocholesta-5,7-dien and 1xcex1,3xcex2,25-trihydroxy-24-oxocholesta-5,7-dien are mentioned in Examples 1, 1, 4, 4, 5ii, 5(1), 6i, 7, 7(2), 8iii, 8iv, 8iv, 9iii and 9iv, respectively. It is mentioned that the compounds described therein are useful intermediates convertible into active vitamin D3.
In European patent application having publication :no. 63,678B1, (24R)-3xcex2,24,25-trihydroxycholest-5-en; (24RS)-3xcex2,24,25-trihydroxycholest-5-en and (24R)-1xcex2,3xcex2,24,25-tetrahydroxycholest-5-en are mentioned in Examples 1e, 3e and 4f, respectively. It is mentioned that the compounds described therein can be used as intermediates in the preparation of vitamin D3 derivatives.
In European patent application having publication no. 322,036A1, 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholesta-8,14-dien-2xcex1,11xcex2-diol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholest-8-en-2xcex1,11xcex2-diol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-2xcex1,3xcex2,11xcex2-triol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-3xcex2,11xcex2-diol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8-en-2xcex1,3xcex2,11xcex2-triol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholest-8-en-3xcex2,11xcex2-diol; 4,4-dimethyl-24-methylenecholest-8-en-2,3xcex2,11xcex2,12xcex1-tetraol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxycholesta-8,14-dien-2xcex1,11xcex2,12xcex1-triol; 4,4-dimethyl-24-methylenecholesta-8,14-dien-2xcex1,3xcex2,11xcex2,12xcex1-tetraol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholest-8-en-2-ol-11-one and mono(4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-2xcex1,11xcex2-diol)-3xcex2-succinate are described in Tables I (1+2), II (5-9) and III (11-14). It is mentioned that the compounds described therein are anti-inflammatory.
In European patent application having publication no. 349,869A2, 1xcex1,3xcex2-dihydroxycholest-5-ene and 1xcex1,3xcex2,24-trihydroxycholest-5-ene are mentioned in Examples 1 and 2, respectively. It is mentioned that the latter compound is useful for the production of 1xcex1,24-dihydroxy-vitamin D3.
In British patent application having publication no. 2,089,810 A, cholesta-5,7-diene-3xcex2,23(R),25-triol and cholesta-5,7-diene-3xcex2,23(S),25-triol are mentioned in Example 1. It is mentioned that the compounds described therein should find application as a substitute for 25-hydroxy vitamin D3 in various therapeutic applications.
In Norwegian patent application having publication no. 144,264, 1xcex1,3xcex2-dihydroxycholest-5-en and 1xcex1,3xcex2,25-trihydroxycholest-5-en are mentioned in Example 1 and 3, respectively. It is mentioned that the compounds described therein can be used within the veterinary field.
In Swedish patent application having publication no. 314,978, a process wherein xcex947-cholesten-2xcex2,3xcex2-diol-6-one is used as starting material (for the preparation of xcex947-koprosten-2xcex2,3xcex2,14xcex1-triol-6-one) is described in Example 3. The latter compound is active against insecticide metamorfose hormones.
In Swedish patent application having publication no. 330,883, 2xcex2,3xcex2, 14xcex1,22(R),25-pentahydroxy-xcex947-5xcex2-cholesten-6-one and 2xcex2,3xcex2,14xcex1,22(S),25-pentahydroxy-xcex947-5xcex2-cholesten-6-one are mentioned in Examples 4 and 5, respectively. It is mentioned that the compounds described therein have valuable pharmacological properties; however, none is specified.
In Swedish patent application having publication no. 430,508, cholest-5-en-3xcex2,22(R,S),25-triol; cholest-5-en-25-fluoro-3xcex2,22(R,S)-diol; cholest-5-en-25-fluoro-22(R,S)-ol-3xcex2-semisuccinate; cholest-5-en-25-chloro-3xcex2,22-diol and cholest-5-en-25-chloro-22-ol-3xcex2-hemisuccinate are mentioned in Examples 5, 8, 9, 11 and 12, respectively. It is mentioned that the compounds described therein have pharmaceutical activities, e.g., inhibiting (HMG-CoA) reductase.
In U.S. Pat. No. 3,931,403, 3xcex1,7xcex1,12xcex1,24,25-pentahydroxy coprostane; 3xcex1,7xcex1, 12xcex1,25-tetrahydroxy coprostane; 3xcex1,7xcex1,25-trihydroxy coprostane; 3xcex1,7xcex1,24,25-tetrahydroxy coprostane; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,24xcex1,25-pentol; 5xcex2-cholestane-3xcex1,7xcex1,-12xcex1,24xcex2,25-pentol; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,25,26-pentol and 5,3cholestane-3xcex1,7xcex1,12xcex1,25-tetrol are mentioned in Examples I and II. It is mentioned that the compounds described therein can be used to prepare a composition possessing antimicrobial, antibiotic and bacteriostatic properties.
In U.S. Pat. No. 4,011,250, 1xcex1,2xcex1,3xcex2-trihydroxycholesta-5,7-diene and 1xcex1,2xcex1-dihydroxy-3xcex2-acetoxycholesta-5-ene are described as intermediates in Example 1 and 3, respectively.
In U.S. Pat. No. 4,254,045, cholest-5-en-2,fluoro-1 a,3,diol is mentioned as compound 3. It is mentioned that the compounds described therein have vitamin D-like activity.
In U.S. Pat. No. 4,329,295, the preparation of 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol-3-acatate, 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol, 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol 3 hydrogen butanedioate and 24-cyclopropyl-5a-cholane-3xcex2,22(S)-diol is described in Examples 3-6, respectively. It is mentioned that the compounds described therein inhibit the activity of HMG Co A reductase.
In U.S. Pat. No. 4,670,190, cholesta-1,4,6-trien-3-one; 1xcex1,3xcex2-dihydroxycholest-5-ene; 1xcex1,3xcex2-dihydroxy-5xcex1-cholestane; 1xcex1,3xcex2-dihydroxycholesta-5,7-diene 1xcex1,3xcex2-25-trihydroxycholest-5-ene; 1xcex1,25-dihydroxycholesterol; and 1xcex1,25-dihydroxycholesterol-3-benzoate are described in Examples 1a, 1c, 2bxe2x80x2, 3c, 4c, 9b and 9c, respectively. It is mentioned that the compounds described therein have therapeutic applications.
Other known compounds are cholest-5-en-35,20(S)-diol (Sigma, St. Louis, Mo, USA, Cat. No. H 6378), cholest-5-en-3p,22(S)-diol, (Sigma, St. Louis, Mo, USA, Cat. No. H 5884), cholest-5-en-3xcex2,4xcex2-diol (Steraloid Inc., Wilton, N.H., USA, Cat. No. C 6410, Batch L 1066), cholest-5-en-3xcex2,22(R)-diol (Sigma, St. Louis, Mo., USA, Cat. No. H 9384) and 2xcex2,3xcex2,14xcex122(R),25-pentahydroxycholest-7-en-6-one.
In none of the above publications is there any mentioning of the compounds being able to regulate meiosis. The content of the above publications is incorporated by reference.
Meiosis is the unique and ultimate event of germ cells on which sexual reproduction is based. Meiosis comprises two meiotic divisions. During the first division, exchange between maternal and paternal genes take place before the pairs of chromosomes are separated into the two daughter cells. These contain only half the number (1 n) of chromosomes and 2c DNA. The second rneiotic division proceeds without a DNA synthesis. This division therefore results in the formation of the haploid germ cells with only 1 c DNA.
The meiotic events are similar in the male and female germ cells, but the time schedule and the differentiation processes which lead to ova and to spermatozoa differ profoundly. All female germ cells enter the prophase of the first meiotic division early in life, often before birth, but all are arrested as oocytes later in the prophase (dictyate state) until ovulation after puberty. Thus, from early life the female has a stock of oocytes which is drawn upon until the stock is exhausted. Meiosis in females is not completed until after fertilization, and results in, only one ovum and two abortive polar bodies per germ cell. In contrast, only some of the male germ cells enter meiosis from puberty and leave a stem population of germ cells throughout life. Once initiated, meiosis in the male cell proceeds without significant delay and produces 4 spermatozoa.
Only little is known about the mechanisms which control the initiation of meiosis in the male and in the female. In the oocyte, new studies indicate that follicular purines, hypoxanthine or adenosine, could be responsible for meiotic arrest (Downs, S. M. et al. Dev Biol 82 (1985) 454-458; Eppig, J.J. et al. Dev Biol 119 (1986) 313-321; and Downs, S. M. Mol Reprod Dev 35 (1993) 82-94). The presence of a diffusible meiosis regulating substance was first described by Byskov et aL in a culture system of fetal mouse gonads (Byskov, A. G. et al. Dev Biol 52 (1976) 193-200). A meiosis activating substance (MAS) was secreted by the fetal mouse ovary in which meiosis was ongoing, and a meiosis preventing substance (MPS) was released from the morphologically differentiated testis with resting, non-meiotic germ cells. It was suggested that the relative concentrations of MAS and MPS regulated the beginning, arrest and resumption of meiosis in the male and in the female germ cells (Byskov, A. G. et al. in The Physiology of Reproduction (eds. Knobil, E. and Neill, J. D., Raven Press, New York (1994)). Clearly, if meiosis can be regulated, reproduction can be controlled. A recent article (Byskov, A. G. et aL Nature 374 (1995), 559-562) describes the isolation from bull testes and from human follicular fluid of certain sterols that activate oocyte meiosis. Unfortunately, these sterols are rather labile and utilization of the interesting finding would thus be greatly facilitated if more stable meiosis activating compounds were available.
Compounds being known to stimulate the meiosis and being different from the compounds claimed in the present patent application are described in WO 96/27658.
The compounds described herein have advantages compared with the known compounds.
It is a purpose of the present invention to provide compounds and methods useful for relieving infertility in females and males, particularly in mammals, more particularly in humans.
It is a further purpose of the present invention to provide compounds and methods useful as contraceptives in females and males, particularly in mammals, more particularly in humans.
According to the present invention there are provided novel compounds with interesting pharmacological properties. In particular, the compounds of formula 1a, 1b and 1c are useful for regulating the meiosisin oocytes and in male germ cells.
In one aspect, the present invention relates to compounds of formula 1a: 
wherein R1 and R2, which are different or identical with the proviso that they are not both hydroxy, are selected fromn the group comprising hydrogen, halogen, hydroxy and branched or unbranched C1-C6alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R1 and R2 together designate methylene or oxo or, together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring; R3 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR26 wherein R26 is hydrogen or C1-C3 alkyl, or R3 designates, together with R9 or R14, an additional bond between the carbon atoms at which R3 and R9 or R14 are placed; R4 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR27 wherein R27 is hydrogen or C1-C3 alkyl, or R4 designates, together with R13 or R15, an additional bond between the carbon atoms at which R4 and R13 or R15 are placed; R5is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, oxo and =NOR22 wherein R22 is hydrogen or C1-C3 alkyl, or R5 designates, together with R6 an additional bond between the carbon atoms at which R5 and R6 are placed; R6 is hydrogen or hydroxy or R6 designates, together with R5, an additional bond between the carbon atoms at which R5 and R6 are placed; R9 is hydrogen, hydroxy, halogen or oxo or R9 designates, together with R3 or R10, an additional bond between the carbon atoms at which R9 and R3 or R10 are placed; R10 is hydrogen, halogen or hydroxy, or R10 designates, together with R9, an additional bond between the carbon atoms at which R10 and R9 are placed; R11 is selected from the group comprising hydroxy, optionally substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR28 wherein R28 is hydrogen or C1-C3 alkyl, or R11 designates, together with R12, an additional bond between the carbon atoms at which R11 and R12 are placed; R12 is selected from the group comprising hydrogen, hydroxy, C1-C3 alkyl, vinyl, C1-C3 alkoxy and halogen, or R12 designates, together with R11, an additional bond between the carbon atoms at which R12 and R11 are placed; R13 is hydrogen, hydroxy or halogen or R13 designates, together with R4 or R14, an additional bond between the carbon atoms at which R13 and R4 or R14 are placed; R14 is hydrogen, hydroxy or halogen, or R14 designates, together with R3, R6 or R13, an additional bond between the carbon atoms at which R4 and R3 or R6or R13 are placed; R15 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo and =NOR23 wherein, R23 is hydrogen or C1-C3 alkyl, or R15 designates, together with R4, an additional bond between the carbon atoms at which R15 and R4 are placed; R16 is selected from the group comprising hydrogen, halogen, C1-C3 alkyl, methylene, hydroxy, methoxy, oxo and =NOR24 wherein R24 is hydrogen or C1-C3 alkyl, or R16 designates, together with R17, an additional bond between the carbon atoms at which R16 and R17 are placed; R17 is hydrogen or hydroxy, or R17 designates, together with R16, an additional bond between the carbon atoms at which R17 and R16 are placed; R18 and R19 are both hydrogen, or one of R18 and R19 is hydrogen while the other is halogen, hydroxy or methoxy, or R18 and R19 together designate oxo; R25 is selected from the group comprising C1-C4 alkyl and hydroxymethyl, or R25 and R31 together designate methylene or oxo; R29 is hydrogen, halogen, methyl, hydroxy or oxo; R30 is hydrogen, halogen, methyl or hydroxy; R31 is hydrogen, halogen, methyl or hydroxy, or R31, together with R25, designates methylene or oxo; and A is a carbon atom or a nitrogen atom; and when A is a carbon atom, R7 is selected from the group comprising hydrogen, hydroxy and halogen; and R8 is selected from the group comprising hydrogen, halogen, hydroxy, C1-C4 alkyl, methylene and oxo, or R7 designates, together with R8, an additional bond between the carbon atoms at which R7 and R8 are placed; R20 is selected from the group comprising C1-C4 alkyl, trifluoromethyl and C3-C6 cycloalkyl, R21 is selected from the group comprising C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C3-C6 cycloalkyl, or R20 and R21, together with the carbon atom at which they are placed, form a C3-C6 cycloalkyl ring; and when A is a nitrogen atom, R7 designates a lone pair of electrons; and R8 is selected from the group comprising hydrogen, hydroxy, C1-C4 alkyl, cyano and oxo; and R20 and R21 are, independently, C1-C4 alkyl or C3-C6 cycloalkyl; with the general proviso that at least one of R1, R2, R6, R8 R9, R10, R12, R13, R14, R18, R19, R29, R30 and R31 is hydroxy or R25 is hydroxymethyl and with the further general proviso that R9, R10 and R11 are not all hydroxy and with the further general proviso that it is not 5xcex1-bromocholestane-3xcex2,6xcex2-diol; 7xcex1-bromo-cholestane-3xcex2,6xcex1-diol; 7xcex1-bromocholestane-3xcex2,6xcex2-diol; 7xcex1-bromocholestane-3xcex2,5xcex1-diol-6-one; 7xcex2-bromocholestane-3xcex2,5xcex1-diol-6-one; 3xcex2-bromocholestane-2xcex1-ol; 5xcex1-chlorocholestane-3xcex2,6xcex1-diol; 5xcex1-chlorocholestane-3xcex2,6xcex2-diol; 6xcex2-chlorocholestane-3xcex2,5xcex1-diol; xcex947,9(11)-cholestadiene-3xcex2-6xcex1-diol; xcex947,9(11)-cholestadiene-3xcex2,6xcex2-diol; cholestane-2xcex1,3xcex1-diol; cholestane-2xcex1,3xcex2-diol; cholestane-2xcex2,3xcex1-diol; cholestane-2xcex2,3xcex2-diol; cholestane-3xcex1,4xcex1-diol; cholestane-3xcex1,4xcex2-diol; cholestane-3xcex2,4xcex2-diol; cholestane-3xcex1,5xcex1-diol; cholestane-3xcex2,5xcex1-diol; cholestane-3xcex2,6xcex1-diol; cholestane-3xcex2,6xcex2-diol; cholestane-3xcex2,22xcex1-diol; cholestane-3xcex2,22xcex2-diol; cholestane-3xcex2,7xcex1,8xcex1-triol; triol; xcex945-cholestene-3xcex2,4xcex1-diol; xcex945-cholestene-3xcex2,4xcex2-diol; xcex945-cholestene-3xcex2,20xcex1-diol; xcex945-cholestane-3xcex2,22xcex1-diol; xcex945-cholestene-3xcex2,22xcex2-diol; xcex945-cholestene-3xcex2,24xcex1-diol; xcex945-cholestene-3xcex2,24xcex2-diol; xcex946-cholestene-3xcex2,5xcex1-diol; xcex948(14)-cholestene-3xcex2,9xcex1-diol; xcex9411-cholestene-3xcex1,24-diol; xcex945-cholestene-3xcex2,6-diol-7-one; xcex945-cholestene-4xcex1-ol-3-one; xcex945-cholestene-3xcex2,4xcex2,7xcex1-triol; coprostane-3xcex1,5xcex2-diol; coprostane-3xcex2,5xcex2-diol; coprostane-3xcex2,6xcex2-diol; coprostane-4xcex25xcex2-diol-3-one; 20xcex2hydroxy-20-isocholesterol; 4xcex1-hydroxy-5xcex1-cholestan-3-one; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate-6pacetate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate-6xcex2-formiate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-sulphate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-phosphate; 2xcex2,3xcex2,14xcex1,22(R),25-pentahydroxycholest-7-en-6-one; cholest-7-en-2xcex2,3xcex2,5xcex2,11xcex1,14xcex1,20(R),22(R)-heptahydroxy-6-one; 5,24-cholestadien-3xcex2-ol; 5-cholesten-3xcex2,24,25-triol-3xcex2-acetate; 5-cholesten-3xcex2,24,25-triol-3xcex2,24-diacetate; 5,25-cholestadien-3xcex2-ol acetate; 5-cholesten-3xcex2,25,26-triol-3xcex2-acetate; 5-cholesten-3xcex2,25,26-triol; 24,25(or 25,26)-dihydroxy-cholecalciferol; cholest-5xcex1-an-3xcex2,6xcex1-diol; cholest-5xcex2-an-3xcex2,6xcex2-diol; cholest-5xcex1-an-3,6-dione; cholest-5xcex1-an-6xcex2-ol-3-one; cholest-5xcex1-an-2xcex1-bromo-6xcex2-ol-3-one; cholestan-3xcex2,25-diol-3xcex2-acetate; cholestan-3xcex2,5xcex1,25-triol-3xcex2-acetate; cholestan-3xcex2,5xcex1,25-triol; cholestan-5xcex1,25-diol-3-one; cholest4-en-25-ol-3-one; cholesta-4,6-dien-25-ol-3-one; 1xcex1,3xcex2-dihydroxycholest-5-en; 1xcex1,3xcex2-dihydroxycholest-6-en; 3xcex1,6xcex1-dihydroxy-5xcex2-cholestan-24-one; 3xcex1,6xcex1,24-trihydroxy-5xcex2cholestan; 3-chlorocholest-5,24-dien; 3xcex2-hydroxycholest-5-en-24-on acetate; 3-chlorocholest-5-en-24-on; cholestan-25-fluoro-3xcex2,22(S)-diol; cholestan-25-chloro-3xcex2,22(S)-diol; cholestan-25-methyl-3xcex2,22-diol; cholestan-25-methyl-3xcex2,22-diol-3-hydrogenbutandioate; cholestan-25-methyl-3xcex2,22-diol-bis-hydrogenbutandioate; 1xcex1,25-dihydroxy-26,26,26,27,27,27-hexafluorocholes-5-en; 2xcex2,3xcex2,14xcex1,22,25-pentahydroxy-xcex947-5xcex2-cholesten-6-one; 25-hydroxy-3xcex2-[(tetrahydro-2H-pyran-2-yl)oxy]cholest-5-en-24-on; 3p-[(tetrahydro-2H-pyran-2-yl)oxy]-cholest-5-en-24-on; 25-hydroxy-24-oxocholesterol-3p-acetate; 24-oxocholesterol-3xcex2-acetate; 25-hydroxy-24-oxocholesterol; 24,25-dihydroxycholesterol; 3x,6a,25-trihydroxy-24-oxo-5xcex2-cholestane; 1xcex1,25-dihydroxy-24-oxocholesterol; 1xcex1,24,25-trihydroxycholesterol; 3xcex2-hydroxy-24-oxocholesta-5,7-dien; 3xcex2,25-dihydroxy-24-oxocholesta-5,7-dien; 3xcex2-hydroxy-24-oxo-cholesta-5,7-dien; 1xcex1,3xcex2-dihydroxy-24-oxocholesta-5,7-dien; 1xcex1,3xcex2,25-trihydroxy-24-oxo-cholesta-5,7-dien; (24R)-3xcex2,24,25-trihydroxycholest-5-en; (24RS)-3xcex2,24,25-trihydroxycholest-5-en; (24R)-1xcex2,3 xcex2, 24,25-tetrahydroxycholest-5-en; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholesta-8,14-dien-2xcex1,11xcex2-diol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholest-8-en-2xcex1,11xcex2-diol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-2xcex1,3xcex2,11xcex2-triol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-3xcex2,11xcex2-diol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholest-8-en-2xcex1,3xcex2,11xcex2-triol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholest-8-en-3xcex211xcex2-diol; 4,4-dimethyl-24-methylenecholest-8-en-2,3xcex2,11xcex2,12xcex1-tetraol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxycholesta-8,14-dien-2xcex1,11xcex2,12xcex1-triol; 4,4-dimethyl-24-methylenecholesta-8,14-dien-2xcex1,3xcex2,11xcex2,12xcex1-tetraol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholest-8-en-2-ol-11-one; mono(4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-2xcex1,11xcex2-diol)-3xcex2-succinate; 1xcex1,3xcex2-dihydroxycholest-5-ene; 1xcex1,3xcex2,24-trihydroxycholest-5-ene; cholesta-5,7-diene-3xcex2,23(R),25-triol; cholesta-5,7-diene-3xcex2,23(S),25-triol; 1xcex1,3xcex2-dihydroxycholest-5-en; 1xcex1,3xcex2,25-trihydroxycholest-5-en; xcex947-cholesten-2xcex2,3xcex2-diol-6-one; 2xcex2,3xcex2,14xcex1,22(R),25-pentahydroxy-xcex947-5xcex2-cholesten-6-one; 2xcex2,3xcex2,14xcex1,22(S),25-pentahydroxy-xcex947-5xcex2-cholesten-6-one; cholest-5-en-3xcex2,22(R,S),25-triol; cholest-5-en-25-fluoro-3xcex2,22(R,S)-diol; cholest-5-en-25-fluoro-22(R,S)-ol-3xcex2-semisuccinate; cholest-5-en-25-chloro-3xcex2,22-diol; cholest-5-en-25-chloro-22-ol-3xcex2-hemisuccinate; 3xcex1,7xcex1,12xcex1,24,25-pentahydroxy coprostane; 3xcex1,7xcex1,12xcex1,25-tetrahydroxy coprostane; 3xcex1,7xcex1,25-trihydroxy coprostane; 3xcex1,7xcex1,24,25-tetrahydroxy coprostane; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,24xcex1,25-pentol; 5xcex2cholestane-3xcex1,7xcex1,12xcex1,24xcex2,25-pentol; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,25,26-pentol; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,25-tetrol; 1xcex1,2xcex1,3xcex2-trihydroxycholesta-5,7-diene; 1xcex1,2xcex1-dihydroxy-3xcex2-acetoxycholesta-5-ene; cholest-5-en-2xcex2-fluoro-1xcex1,3xcex2diol; 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol-3-acatate, 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol, 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol 3 hydrogen butanedioate; 24-cyclopropyl-5xcex1-cholane-3xcex2,22(S)-diol; cholesta-1,4,6-trien-3-one; 1xcex1,3xcex2-dihydroxycholest-5-ene; 1xcex1,3xcex2-dihydroxy-5xcex1-cholestane; 1xcex1,3xcex2-dihydroxycholesta-5,7-diene; 1xcex1,3xcex2-25-trihydroxycholest-5-ene; 1xcex1,25-dihydroxycholesterol; 1xcex1,25-dihydroxycholesterol-3-benzoate; cholest-5-en-3xcex2,20(S)-diol; 2xcex2,3xcex2,14xcex1,22(R),25-pentahydroxycholest-7-en-6-one and cholest-5-en-3xcex2,22(S)-diol; cholest-5-en-3xcex2,20(S)-diol; cholest-5-en-3xcex2,22(S)-diol; cholest-5-en-3xcex2,4xcex2-diol; cholest-5-en-3xcex2,22(R)-diol and 2xcex2,3xcex2,14xcex1,22(R),25-pentahydroxy-cholest-7-en-6-one.
In another embodiment, the invention relates to esters of compound of formula Ia. Such esters are formally derived by esterification of one or more hydroxylic groups of a compound of formula Ia with an acid which, for example, can be selected from the group of acids comprising succinic acid and other aliphatic dicarboxylic acids, nicotinic acid, isonicotinic acid, ethylcarbonic acid, phosphoric acid, sulphonic acid, sulphamic acid, benzoic acid, acetic acid, propionic acid and other aliphatic monocarboxylic acids.
In still another preferred embodiment, the present invention relates to compounds of formula Ib and esters thereof as a medicament.
Compounds of formula Ib have the following structural formula: 
wherein R1 and R2, which are different or identical with the proviso that they are not both hydroxy, are selected from the group comprising hydogen, halogen, hydroxy and branched or unbranched C1-C6alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R1 and R2 together designate methylene or oxo or, together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring; R3is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and xe2x95x90NOR26 wherein R26 is hydrogen or C1-C3 alkyl, or R3 designates, together with R9 or R14, an additional bond between the carbon atoms at which R3 and R9 or R14 are placed; R4 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR27 wherein R27 is hydrogen or C1-C3 alkyl, or R4 designates, together with R13 or R15, an additional bond between the carbon atoms at which R4 and R13 or R15 are placed; R5 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, oxo and xe2x95x90NOR22 wherein R22 is hydrogen or C1-C3 alkyl, or R5 designates, together with R6 an additional bond between the carbon atoms at which R5 and R6 are placed; R6 is hydrogen or hydroxy or R6 designates, together with R5, an additional bond between the carbon atoms at which R5 and R6 are placed; R9 is hydrogen, hydroxy, halogen or oxo or R9 designates, together with R3 or R10, an additional bond between the carbon atoms at which R9 and R3 or R10 are placed; R10 is hydrogen, halogen or hydroxy, or R10 designates, together with R9, an additional bond between the carbon atoms at which R10 and R9 are placed; R11 is selected from the group comprising hydroxy, optionally substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and xe2x95x90NOR28 wherein R28 is hydrogen or C1-C3 alkyl, or R11 designates, together with R12, an additional bond between the carbon atoms at which R11 and R12 are placed; R12 is selected from the group comprising hydrogen, hydroxy, C1-C3 alkyl, vinyl, C1-C3 alkoxy and halogen, or R12 designates, together with R11, an additional bond between the carbon atoms at which R12 and R11 are placed; R13 is hydrogen, hydroxy or halogen or R13 designates, together with R4 or R4, an additional bond between the carbon atoms at which R13 and R4 or R14 are placed; R14 is hydrogen, hydroxy or halogen, or R14 designates, together with R3, R6 or R3, an additional bond between the carbon atoms at which R14 and R3 or R6 or R13 are placed; R15 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo and xe2x95x90NOR23 wherein R23 is hydrogen or C1-C3 alkyl, or R15 designates, together with R4, an additional bond between the carbon atoms at which R15 and R4 are placed; R16 is selected from the group comprising hydrogen, halogen, C1-C3 alkyl, methylene, hydroxy, methoxy, oxo and xe2x95x90NOR24 wherein R24 is hydrogen or C1-C3 alkyl, or R16 designates, together with R17, an additional bond between the carbon atoms at which R16 and R17 are placed; R17 is hydrogen or hydroxy, or R17 designates, together with R16, an additional bond between the carbon atoms at which R17 and R16 are placed; R18 and R19 are both hydrogen, or one of R18 and R19 is hydrogen while the other is halogen, hydroxy or methoxy, or R18 and R19 together designate oxo; R25 is selected from the group comprising C1-C4 alkyl and hydroxymethyl, or R25 and R31 together designate methylene or oxo; R29 is hydrogen, halogen, methyl, hydroxy or oxo; R30 is hydrogen, halogen, methyl or hydroxy; R31 is hydrogen, halogen, methyl or hydroxy, or R31, together with R25, designates methylene or oxo; and A is a carbon atom or a nitrogen atom; and when A is a carbon atom, R7 is selected from the group comprising hydrogen, hydroxy and halogen; and R8 is selected from the group comprising hydrogen, halogen hydroxy, C1-C4 alkyl, methylene and oxo, or R7 designates, together with R8, an additional bond between the carbon atoms at which R7 and R3 are placed; R20 is selected from the group comprising C1-C4 alkyl, trifluoromethyl and C3-C6 cycloalkyl; R21 is selected from the group comprising C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C3-C6 cycloalkyl, or R20 and R21, together with the carbon atom at which they are placed, form a C3-C6 cycloalkyl ring; and when A is a nitrogen atom, R7 designates a lone pair of electrons; and R8 is selected from the group comprising hydrogen, hydroxy, C1-C4 alkyl, cyano and oxo; and R20 and R21 are, independently, C1-C4 alkyl or C3-C6 cycloalkyl; with the general proviso that at least one of R1, R2, R6 R8, R9, R10, R12, R13, R14, R18, R19, R29, R30 and R31 is hydroxy or R25 is hydroxymethyl, with the further general proviso that R9, R10 and R11 are not all hydroxy, and with the further general proviso that it is not cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate-6xcex2-acetate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemi-succinate-6xcex2-formiate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-sulphate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-phosphate; cholestan-3xcex2,25-diol-3xcex2-acetate; cholestan-3xcex2,5xcex1,25-triol-3xcex2-acetate; cholestan-3xcex2,5xcex1,25-triol; cholestan-5xcex1,25-diol-3-one; cholest-4-en-25-ol-3-one; cholesta-4,6-dien-25-ol-3-one; 1xcex1,3xcex2-dihydroxycholest-5-en; 1xcex1,3xcex2-dihydroxycholest-6-en; 3xcex1,6xcex1-dihydroxy-5xcex2-cholest-an-24-one; 3xcex1,6xcex1,24-trihydroxy-5xcex2-cholestan; 3-chlorocholest-5,24-dien; 3xcex2-hydroxycholest-5-en-24-on acetate; 3-chlorocholest-5-en-24-on; cholestan-25-fluoro-3xcex2,22(S)-diol; cholestan-25-chloro-3xcex2,22(S)-diol; cholestan-25-methyl-3xcex2,22-diol; cholestan-25-methyl-3xcex2,22-diol-3-hydrogenbutandioate; cholestan-25-methyl-3xcex2,22-diol-bis-hydrogenbutandioate; 2xcex2,3xcex2,14xcex1,-22,25-pentahydroxy-xcex947-5xcex2-cholesten-6-one; (24R)-3xcex2,24,25-trihydroxycholest-5-en; (24RS)-3xcex2,24,25-trihydroxycholest-5-en; (24R)-1xcex2,3xcex2,24,25-tetrahydroxycholest-5-en; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholesta-8,14-dien-2xcex1,11xcex2-diol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholest-8-en-2xcex1,11xcex2-diol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-2xcex1,3xcex2,11xcex2-triol; 4,4-dimethyl-24-methylene-12xcex1-acetoxy-cholesta-8,14-dien-3xcex2,11xcex2-diol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholest-8-en-2xcex1,3xcex2-11xcex2-triol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholest-8-en-3xcex2,11xcex2-diol; 4,4-dimethyl-24-methylenecholest-8-en-2,3xcex2,11xcex2,12xcex1-tetraol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-cholesta-8,14-dien-2xcex1,11xcex2,12xcex1-triol; 4,4-dimethyl-24-methylenecholesta-8,14-dien-2xcex1,3xcex2,-11xcex2,12xcex1-tetraol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholest-8-en-2-ol-11-one; mono(4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-2xcex1,11xcex2-diol)-3xcex2-succinate; cholesta-5,7-diene-3xcex2,23(R),25-triol; cholesta-5,7-diene-3xcex2,23(S),25-triol; 2xcex2,3xcex2,-14xcex1,22(R),25-pentahydroxy-xcex947-5xcex2-cholesten-6-one; 2xcex2,3xcex2,14xcex1,22(S),25-pentahydroxy-xcex947-5xcex2-cholesten-6-one; cholest-5-en-3xcex2,22(R,S),25-triol; cholest-5-en-25-fluoro-3xcex2,22(R,S)-diol; cholest-5-en-25-fluoro-22(R,S)-ol-3xcex2-semisuccinate; cholest-5-en-25-chloro-3xcex2,22-diol; cholest-5-en-25-chloro-22-ol-3xcex2-hemisuccinate; 3xcex1,7xcex1,12xcex1,24,25-pentahydroxy coprostane; 3xcex1,7xcex1,-12xcex1,25-tetrahydroxy coprostane; 3xcex1,7xcex1,25-trihydroxy coprostane; 3xcex1,7xcex1,24,25-tetrahydroxy coprostane; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,24xcex1,25-pentol; 5xcex2-cholestane-3xcex1, 7xcex1,12xcex1,24xcex2,25-pentol; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,25,26-pentol; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,25-tetrol; cholest-5-en-2xcex2-fluoro-1xcex1,3xcex2-diol; 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol-3-acatate, 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol, 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol 3 hydrogen butanedioate; 24-cyclo-propyl-5xcex1-cholane-3xcex2,22(S)-diol; cholesta-1,4,6-trien-3-one; 1xcex1,3xcex2-dihydroxycholest-5-ene; 1xcex1,3xcex2-dihydroxy-5xcex1-cholestane; 1xcex1,3xcex2-dihydroxycholesta-5,7-diene; 1xcex1,3xcex2-25-trihydroxy-cholest-5-ene; 1xcex1,25-dihydroxycholesterol; and 1xcex1,25-dihydroxycholesterol-3-benzoate, as a medicament.
In a further preferred embodiment, this invention relates to compounds of formula Ic or esters thereof in the manufacture of a medicament for use in the regulation of meiosis.
Compounds of formula Ic have the following structural formula: 
wherein R1 and R2, which are different or identical with the proviso that they are not both hydroxy, are selected from the group comprising hydrogen, halogen, hydroxy and branched or unbranched C1-C6 alkyI which may be substituted by halogen, hydroxy or cyano, or wherein R1 and R2 together designate methylene or oxo or, together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring; R3 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and xe2x95x90NOR26 wherein R26 is hydrogen or C1-C3 alkyl, or R3 designates, together with R9 or R14, an additional bond between the carbon atoms at which R3 and R9 or R14 are placed; R4 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and xe2x95x90NOR27 wherein R27 is hydrogen or C1-C3 alkyl, or R4 designates, together with R13 or R15, an additional bond between the carbon atoms at which R4 and R13 or R15 are placed; R5 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, oxo and xe2x95x90NOR22 wherein R22 is hydrogen or C1-C3 alkyl, or R5 designates, together with R6 an additional bond between the carbon atoms at which R5 and R6 are placed; R6 is hydrogen or hydroxy or R6 designates, together with R5, an additional bond between the carbon atoms at which R5 and R6 are placed; R9 is hydrogen, hydroxy, halogen or oxo or R9 designates, together with R3 or R10, an additional bond between the carbon atoms at which R9 and R3 or R10 are placed; R10 is hydrogen, halogen or hydroxy, or R10 designates, together with R9, an additional bond between the carbon atoms at which R10 and R9 are placed; R11 is selected from the group comprising hydroxy, optionally substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and xe2x95x90NOR28 wherein R28 is hydrogen or C1-C3 alkyl, or R11 designates, together with R12, an additional bond between the carbon atoms at which R11 and R12 are placed; R12 is selected from the group comprising hydrogen, hydroxy, C1-C3 alkyl, vinyl, C1-C3 alkoxy and halogen, or R12 designates, together with R11, an additional bond between the carbon atoms at which R12 and R11 are placed; R13 is hydrogen, hydroxy or halogen or R13 designates, together with R4 or R14, an additional bond between the carbon atoms at which R13 and R4 or R4 are placed; R14 is hydrogen, hydroxy or halogen, or R14 designates, together with R3, R6 or R13, an additional bond between the carbon atoms at which R14 and R3 or R6or R13 are placed; R15 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo and xe2x95x90NOR23 wherein R23 is hydrogen or C1-C3 alkyl, or R15 designates, together with R4, an additional bond between the carbon atoms at which R15 and R4 are placed; R16 is selected from the group comprising hydrogen, halogen, C1-C3 alkyl, methylene, hydroxy, methoxy, oxo and xe2x95x90NOR24 wherein R24 is hydrogen or C1-C3 alkyl, or R16 designates, together with R17, an additional bond between the carbon atoms at which R16 and R17 are placed; R17 is hydrogen or hydroxy, or R17 designates, together with R16, an additional bond between the carbon atoms at which R17 and R18 are placed; R18 and R19 are both hydrogen, or one of R18 and R19 is hydrogen while the other is halogen, hydroxy or methoxy, or R18 and R19 together designate oxo; R25 is selected from the group comprising C1-C4 alkyl and hydroxymethyl, or R25 and R31 together designate methylene or oxo; R29 is hydrogen, halogen, methyl, hydroxy or oxo; R30 is hydrogen, halogen, methyl or hydroxy; R31 is hydrogen, halogen, methyl or hydroxy, or R31, together with R25, designates methylene or oxo; and A is a carbon atom or a nitrogen atom; and when A is a carbon atom, R7 is selected from the group comprising hydrogen, hydroxy and halogen; and R8 is selected from the group comprising hydrogen, halogen, hydroxy, C1-C4 alkyl, methylene and oxo, or R7 designates, together with R8, an additional bond between the carbon atoms at which R7 and R8 are placed; R20 is selected from the group comprising C1-C4 alkyl, trifluoromethyl and C3-C6 cycloalkyl; R21 is selected from the group comprising C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C3-C6 cycloalkyl, or R20 and R21, together with the carbon atom at which they are placed, form a C3-C6 cycloalkyl ring; and when A is a nitrogen atom, R7 designates a lone pair of electrons; and R8 is selected from the group comprising hydrogen, hydroxy, C1-C4 alkyl, cyano and oxo; and R20 and R21 are, independently, C1-C4 alkyl or C3-C6 cycloalkyl; with the general proviso that at least one of R1, R2, R6, R8, R9, R10, R12, R13, R14, R18, R19, R29, R30 and R31 is hydroxy or R25 is hydroxymethyl, and with the further general proviso that R9, R10 and R11 are not all hydroxy and with the further general proviso that it is not, for use in the regulation of meiosis.
In a further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof as a medicament, in particular as a medicament for use in the regulation of meiosis. The compound may be used neat or in the form of a liquid or solid composition containing auxiliary ingredients conventionally used in the art.
In the present context, the expression xe2x80x9cregulating the meiosisxe2x80x9d is used to indicate that certain of the compounds of the invention can be used for stimulating the meiosis in vitro, in vivo, or ex vivo. Thus, the compounds which may be agonists of a naturally occurring meiosis activating substance, can be used in the treatment of infertility which is due to insufficient stimulation of meiosis in females and in males. Other compounds of the invention, which may be antagonists of a naturally occurring meiosis activating substance, can be used for regulating the meiosis, preferably in vivo, in a way which makes them suited as contraceptives. In this case the xe2x80x9cregulationxe2x80x9d means partial or total inhibition.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the regulation of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the stimulation of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the inhibition of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the regulation of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the stimulation of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the inhibition of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.
In a yet still further preferred aspect, the present invention relates to a meth od of regulating the meiosis in a mammalian germ cell which method comprises administering an effective amount of a compound of formula Ic above or an ester thereof to a germ cell in need of such a treatment.
In a still further aspect, the present invention relates to a me thod of regulating the meiosis in a mammalian germ cell wherein a compound of formula Ic above or an ester thereof is administered to the germ cell by administering the compound to a mammal hosting said cell.
In a still further aspect, the present invention relates to a method wherein the germ cell the meiosis of which is to be regulated by means of a compound of formula Ic above or an ester thereof is an oocyte.
In a still further aspect, the present invention relates to a method of regulating the meiosis in an oocyte wherein a compound of formula Ic above or an ester thereof is administered to the oocyte ex vivo.
In a still further aspect, the present invention relates to a method of regulating the meiosis of a male germ cell by administering a compound of formula Ic above or an ester thereof to the cell.
In a still further aspect, the present invention relates to a method whereby mature male germ cells are produced by administering in vivo or in vitro a compound of formula Ic above or an ester thereof to testicular tissue containing immature cells.